CN110577525A - preparation method of vernetulara intermediate - Google Patents
preparation method of vernetulara intermediate Download PDFInfo
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- CN110577525A CN110577525A CN201810594467.1A CN201810594467A CN110577525A CN 110577525 A CN110577525 A CN 110577525A CN 201810594467 A CN201810594467 A CN 201810594467A CN 110577525 A CN110577525 A CN 110577525A
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- pyridine
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- benzoate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to the field of pharmaceutical chemistry, and mainly relates to a vernetulara intermediate (I) methyl 2- (1H-pyrrole [2, 3-B)]Preparation of pyridine-5-oxy) -4- (piperazin-1-yl) benzoate: 2-fluoro-4-bromobenzoic acid methyl ester and 1H-pyrrolo [2,3-B]After the pyridine-5-alcohol is in butt joint with piperazine under the action of a catalyst, the target compound is prepared.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and mainly relates to a preparation method of a vernitoram intermediate (I) methyl 2- (1H-pyrrole [2,3-B ] pyridine-5-oxyl) -4- (piperazine-1-yl) benzoate.
Background
Venetosala (IV) is an experimental B-cell lymphoma factor-2 (BCL-2) inhibitor, developed jointly by Eberella and Roche. BCL-2 is a protein that prevents apoptosis in some cells, including lymphocytes. Venetocalax is aimed at selectively inhibiting the function of BCL-2 factor, restoring cell communication system and self-destroying cancer cell so as to obtain the effect of curing tumor. In 2016, the united states Food and Drug Administration (FDA) has approved Venclexta monotherapy for Chronic Lymphocytic Leukemia (CLL) patients who carry a 17p deletion mutation (del 17 p) and who have previously received at least one therapy.
Methyl 2- (1H-pyrrole [2,3-B ] pyridine-5-oxy) -4- (piperazine-1-yl) benzoate (I) is an important intermediate fragment of vernital and has an important function in the synthesis of vernital.
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Disclosure of Invention
The invention provides a preparation method shown in formula I, which is characterized in that 2-fluoro-4-methyl bromobenzoate is used as a raw material, and methyl 2- (1H-pyrrole [2,3-B ] pyridine-5-oxyl) -4- (piperazine-1-yl) benzoate is prepared through 2-step butt reaction.
The preparation method comprises the following two steps:
(1) Preparing methyl 2- (1H-pyrrolo [2,3-B ] pyridine-5-oxy) -4- (bromo-1-yl) benzoate (II) from methyl 2-fluoro-4-bromobenzoate (III) and 1H-pyrrolo [2,3-B ] pyridine-5-alcohol in an organic solvent in the presence of an organic solvent and an acid-binding agent;
(2) Methyl 2- (1H-pyrrole [2,3-B ] pyridine-5-oxy) -4- (bromo-1-yl) benzoate (II) and anhydrous piperazine react under the conditions of an organic solvent, an acid-binding agent and a palladium catalyst to prepare methyl 2- (1H-pyrrole [2,3-B ] pyridine-5-oxy) -4- (piperazine-1-yl) benzoate (I).
Wherein the organic solvent used in the step 1 is dimethyl sulfoxide, toluene and xylene, and the dimethyl sulfoxide is preferred;
The acid-binding agent used in the step 1 is sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, wherein the sodium hydroxide is preferred;
The reaction temperature in the step 1 is 100-120 ℃, wherein the reaction temperature is preferably 120 ℃;
the organic solvent used in the step 2 is dimethyl sulfoxide, toluene and xylene, wherein the xylene is preferred;
The acid-binding agent used in the step 2 is sodium tert-butoxide, potassium tert-butoxide, sodium hydride and potassium hydride, wherein potassium tert-butoxide is preferred;
The palladium catalyst used in the step 2 is a mixed catalyst of tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, wherein the bis (dibenzylideneacetone) palladium and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are optimized;
The invention has the characteristic of simple operation.
the reagent used in the invention is a conventional reagent, and has little pollution to the environment.
The reagent used in the invention is a conventional reagent, and is cheap and easy to obtain.
The invention can be used for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention thereto.
example 1: preparation of methyl 2- (1H-pyrrolo [2,3-B ] pyridin-5-yloxy) -4- (bromo-1-yl) benzoate
Weighing 2.33kg of 2-fluoro-4-methyl bromobenzoate, dissolving in 14kg of toluene, adding 388.3g of sodium hydroxide under the stirring state, heating to more than 110 ℃, stirring to a sodium hydroxide molten state, dissolving 1.6kg of 1H-pyrrolo [2,3-B ] pyridine-5-alcohol in 3.2kg of dimethyl sulfoxide, slowly dropwise adding into the system, obviously stopping heating when the system releases heat in the dropwise adding process, performing reflux reaction for 4-6H after the addition is finished, monitoring the complete reaction of the 2-fluoro-4-methyl bromobenzoate by TLC, washing the liquid after cooling, adjusting the pH to be neutral by using dilute hydrochloric acid, and directly performing the next operation without treating the solution.
Example 2: preparation of methyl 2- (1H-pyrrolo [2,3-B ] pyridin-5-yloxy) -4- (piperazin-1-yl) benzoate
36.6g Pd (dba) were dissolved in 14kg toluene279.2 g of rac-BINAP and 1.15kg of NaOBut, 1.1kg of piperazine was added into the system, the solution obtained in example 1 was added dropwise into the system, after the addition, the mixture was heated under reflux and stirred for 3 to 4 hours, and the methyl 2- (1H-pyrrole [2,3-B ] was monitored by HPLC]Stopping the reaction when the content of pyridine-5-oxy) -4- (bromo-1-yl) benzoate is lower than 0.2%, adding 23.3kg of distilled water into the system when the temperature is reduced to room temperature, continuing stirring for 1h, performing suction filtration, separating filtrate, washing with 10kg of saturated saline solution twice each time, performing rotary evaporation on an organic phase to obtain 4.08kg of dark brown oily liquid, adding 19.2kg of ethyl acetate, stirring for crystallization, and performing suction filtration to obtain 2.81kg of white crystalline solid, wherein the yield is 79.8% and the HPLC is 99.4%.
Claims (8)
1. a method for preparing methyl 2- (1H-pyrrole [2,3-B ] pyridine-5-oxy) -4- (piperazine-1-yl) benzoate, which is characterized by comprising the following steps:
Step 1: preparing methyl 2- (1H-pyrrolo [2,3-B ] pyridine-5-oxy) -4- (bromo-1-yl) benzoate (II) from methyl 2-fluoro-4-bromobenzoate (III) and 1H-pyrrolo [2,3-B ] pyridine-5-alcohol in an organic solvent in the presence of an organic solvent and an acid-binding agent;
Step 2: methyl 2- (1H-pyrrole [2,3-B ] pyridine-5-oxy) -4- (bromo-1-yl) benzoate (II) and anhydrous piperazine react under the conditions of an organic solvent, an acid-binding agent and a palladium catalyst to prepare methyl 2- (1H-pyrrole [2,3-B ] pyridine-5-oxy) -4- (piperazine-1-yl) benzoate (I).
2. the method of claim 1, further comprising: the organic solvent used in the step 1 is dimethyl sulfoxide, toluene and xylene, wherein the dimethyl sulfoxide is preferred.
3. The method of claim 1, further comprising: the acid-binding agent used in the step 1 is sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide, wherein sodium hydroxide is preferred.
4. the method of claim 1, further comprising: the reaction temperature in step 1 is 100-120 ℃, wherein the reaction temperature is preferably 120 ℃.
5. the method of claim 1, further comprising: the organic solvent used in step 2 is dimethyl sulfoxide, toluene or xylene, wherein xylene is preferred.
6. the method of claim 1, further comprising: the acid-binding agent used in the step 2 is sodium tert-butoxide, potassium tert-butoxide, sodium hydride and potassium hydride, wherein potassium tert-butoxide is preferred.
7. The method of claim 1, further comprising: the palladium catalyst used in the step 2 is a mixed catalyst of tris (dibenzylideneacetone) dipalladium, bis (dibenzylideneacetone) palladium and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine, wherein bis (dibenzylideneacetone) palladium and 1,1 '-binaphthyl-2, 2' -bisdiphenylphosphine are optimized.
8. The method of claim 1, further comprising: the reaction temperature in the step 2 is 100-120 ℃, wherein the reaction temperature is preferably 120 ℃.
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| CN201810594467.1A CN110577525A (en) | 2018-06-11 | 2018-06-11 | preparation method of vernetulara intermediate |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104370905A (en) * | 2014-10-22 | 2015-02-25 | 南京友杰医药科技有限公司 | Synthesis of Bcl-2 inhibitor ABT-199 |
| CN105026394A (en) * | 2013-03-14 | 2015-11-04 | 艾伯维公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
| WO2017156398A1 (en) * | 2016-03-10 | 2017-09-14 | Assia Chemical Industries Ltd. | Solid state forms of venetoclax and processes for preparation of venetoclax |
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2018
- 2018-06-11 CN CN201810594467.1A patent/CN110577525A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105026394A (en) * | 2013-03-14 | 2015-11-04 | 艾伯维公司 | Apoptosis-inducing agents for the treatment of cancer and immune and autoimmune diseases |
| CN104370905A (en) * | 2014-10-22 | 2015-02-25 | 南京友杰医药科技有限公司 | Synthesis of Bcl-2 inhibitor ABT-199 |
| WO2017156398A1 (en) * | 2016-03-10 | 2017-09-14 | Assia Chemical Industries Ltd. | Solid state forms of venetoclax and processes for preparation of venetoclax |
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Application publication date: 20191217 |